Method for treating a subject having neuromuscular impairment of the diaphragm

ABSTRACT

A method for treating a subject is provided where at least two types of electrical stimulation are provided to cause diaphragm contraction. At least one type of stimulation is configured to bias lung volume of a subject. The stimulation method may include without being limited to a method to treat a subject having neuromuscular impairment of the diaphragm. The stimulation method may also include without being limited to a method to treat a subject who has been diagnosed with central sleep apnea.

RELATED APPLICATION DATA

This application claims priority of U.S. Provisional Application Ser.No. 60/876,632 filed Dec. 22, 2006 and is a continuation in part of U.S.application Ser. No. 11/981,342 filed Oct. 31, 2007, which is acontinuation in part of U.S. application Ser. No. 11/480,074 filed Jun.29, 2006, which is a continuation in part of U.S. application Ser. No.11/271,726 filed Nov. 10, 2005 which is a continuation in part of U.S.application Ser. No. 10/966,484 filed Oct. 15, 2004; U.S. applicationSer. No. 10/966,474, filed Oct. 15, 2004; U.S. application Ser. No.10/966,421, filed Oct. 15, 2004; and U.S. application Ser. No.10/966,472 filed Oct. 15, 2004 which are continuations in part of U.S.application Ser. No. 10/686,891 filed Oct. 15, 2003 entitled: BREATHINGDISORDER DETECTION AND THERAPY DELIVERY DEVICE AND METHOD

BACKGROUND

Devices and methods for creating a lung volume bias and/or increasingfunctional residual capacity have been disclosed in one or more of thefollowing application: U.S. application Ser. No. 11/981,342 filed Oct.31, 2007, which is a continuation in part of U.S. application Ser. No.11/480,074 filed Jun. 29, 2006, which is a continuation in part of U.S.application Ser. No. 11/271,726 filed Nov. 10, 2005 which is acontinuation in part of U.S. application Ser. No. 10/966,484 filed Oct.15, 2004; U.S. application Ser. No. 10/966,474, filed Oct. 15, 2004;U.S. application Ser. No. 10/966,421, filed Oct. 15, 2004; and U.S.application Ser. No. 10/966,472 filed Oct. 15, 2004 which arecontinuations in part of U.S. application Ser. No. 10/686,891 filed Oct.15, 2003 entitled: BREATHING DISORDER DETECTION AND THERAPY DELIVERYDEVICE AND METHOD all of which are incorporated herein by reference intheir entirety. One or more of these applications also disclose a numberof different applications for creating lung volume bias and/orincreasing functional residual capacity.

SUMMARY

The present invention provides a device and method for providingelectrical stimulation to elicit a diaphragm response. Among otherthings, one aspect of the invention provides a device and method forelectrical stimulation to cause a lung volume bias. According to oneaspect a lung volume bias augments lung volume during exhalation orinspiration and exhalation. According to one aspect, biased lung volumeis superimposed on respiration. According to another aspect biased lungvolume may be provided by causing a long slow increase in volume.According to one aspect the lung volume bias provides a therapeuticincrease in airway traction. According to one aspect, lung volume biasprovides a changing in lung volume over which intrinsic breathing mayoccur. In accordance with one aspect of the invention electricalstimulation may be provided directly or indirectly to the phrenic nerveand/or diaphragm of a subject. In accordance with one aspect of theinvention treatment may be provided for a number of diseases, disordersand conditions that may relate to, have co-morbidities with, affect, beaffected by respiratory or lung health status, respiration, ventilation,or blood gas levels. Such diseases and disorders may include but are notlimited to obstructive respiratory disorders, upper airway resistancesyndrome, snoring, obstructive apnea; central respiratory disorders,central apnea; hypopnea, hypoventilation, obesity hypoventilationsyndrome other respiratory insufficiencies, inadequate ventilation orgas exchange, chronic obstructive pulmonary diseases; asthma; emphysema;chronic bronchitis; circulatory disorders; hemodynamic disorders;hypertension; heart disease; chronic heart failure; cardiac rhythmdisorders; obesity or injuries in particular affecting breathing orventilation.

Among other things, an aspect of the invention provides a device andmethod for electrical stimulation to increase functional residualcapacity of a subjects lungs. Such increase in functional residualcapacity according to one aspect may be a lung volume bias. Theinvention also provides a device and method for electrical stimulationto create caudal traction on the upper airway by increasing lung volumeor functional residual capacity, thereby stabilizing the airway and/orimproving upper airway patency. The invention also provides stimulationtechniques for avoiding diaphragm fatigue, improving patient comfort,reducing undesired affects of stimulation such as upper airway closure,selecting stimulation parameters, selecting therapy type providingindividualized treatment and/or diagnostics, adjusting stimulation,and/or improving battery life. The present invention also providespreventative or ameliorative treatment for diseases disorders orconditions. The present invention also provides improved stimulation forone or more diseases, disorders or conditions.

In accordance with one aspect of the invention slow gradual ramping upof stimulation is provided over the course of a period of time greaterthan a period of one inspiration cycle, or over the course of timespanning multiple breaths, to gradually increase lung volume, provide alung volume bias, and/or increase functional residual capacity.Stimulation may be ramped down as well. Among other things, the gradualramping of stimulation may provide greater patient comfort, reduce alikelihood of arousal from stimulation, or may reduce sudden change innegative pressure as seen by to upper airway and thereby avoid upperairway closure during stimulation. Thus according to the inventionstimulation provides a slow and/or gradual increase in lung volume. Oneor more stimulation parameters may be ramped including, e.g., pulseamplitude, frequency, pulse width, burst duration and/or burstfrequency.

According to one aspect of the invention stimulation is alternatedbetween hemidiaphragms to allow rest or prevent adaptation. Stimulationmay be separately applied or otherwise controlled to each hemidiaphragm,by turning on or off stimulation or by changing stimulation parametersfor one or both of the hemidiaphragms. The timing may also be separatelycontrolled. Initialization, selection or application of stimulationparameters for each diaphragm may also be separate.

Similarly, stimulation may be alternated or rotated from one electrodeor electrode pair (or group) to another in a multiple electrodeassembly. Stimulation may be altered on the same hemidiaphragm oropposite hemidiaphragms.

Stimulation to each hemidiaphragm or each electrode (or electrode pair)may be ramped up and down separately or, for example one may be rampedup while the other is ramped down to provide a smoother transition andproduce gradual changes in lung volume or other respiration parameterswhen switching stimulation from one hemidiaphragm to the other or fromone electrode or electrode pair to another. Also one side may bestimulated first and then the other side to provide a more gradualincrease in volume. Similarly a gradual ramp down may be provided byreducing stimulation to one hemidiaphragm and then the other.

In accordance with one aspect of the invention, stimulation is providedby varying one or more stimulation parameters, e.g., amplitudes,frequencies, pulse widths and/or burst durations or burst frequencies,to avoid fatigue or adaptation. Such stimulation parameters may bewithin a desired range or may be altered to provide an optimization ofdiaphragm rest and diaphragm activation. Such stimulation protocol maybe generally open loop where a predetermined program or sequence is usedfor preset time periods to stimulate and also provide rest. Stimulationmay be cycled through different amplitudes and/or frequencies or otherparameters. Such stimulation protocol may also be generally closed loopwhere stimulation parameters are adjusted based on feedback indicatingrest is needed or that adaptation is occurring. Stimulation may also beadjusted or cycled on or off depending upon a patient status, such as,for example, sleep state status, response to therapy, or other conditionor status. Such protocol may be either open loop, closed loop or acombination thereof, e.g., wherein stimulation is provided for a periodof time according to a protocol and then sensing is used to periodicallydetermine stimulation and response status. For example, after a periodof stimulation, detection or sensing may be used to determine ifbreathing is continuing to be stabilized after stimulation. Stabilizedventilation may be detected, for example, using methods and devices thatdetermine variations in lung volume, tidal volume, functional residualcapacity, flow, or other respiration parameter. Stimulation may beprovided again when breathing stabilization has fallen off.

Stimulation may be individualized on a patient by patient basis bydetermining individual patient response to stimulation to result in anoptimal or preferred functional residual lung volume or a sustained lungvolume bias, to get a desired result. Detection as well as stimulationmay be optimized or selected on a patient by patient basis where patientstability markers are determined e.g. using polysomnography data (fordevice initialization and/or device programming updating). Suchinitialization may provide a determination of functional residualcapacity or change in functional residual capacity resulting fromstimulation. Accordingly, a baseline functional residual capacity issensed or observed as a reference point, stimulation is provided andresponse or change in FRC produced by the stimulation is sensed orobserved. Functional residual capacity may be observed before, duringand after stimulation. Such observation of stimulation and response maybe while subject is awake or during sleep. A number of polysomnographymarkers may be used to determine effectiveness of stimulation such as:(volume changes, stability of flow, FRC, volume, arousals, arousals inresponse to or due to stimulation). To reduce arousals due tostimulation, stimulation parameters may be modified such as stimulationfrequency, stimulation amplitude or stimulation ramping. Alsostimulation to one or other hemidiaphragm may be adjusted to provide amore gradual affect from stimulation. Other information may be used todetermine adaptation to stimulation where the stimulation may be eithermore effective or less effective, or fatigue where the stimulation isless effective. Modification of stimulation parameters may be providedin response to such fatigue or adaptation. Such device initializationmay be provided with external or temporary sensors, for example in apolysomnography study, or where appropriate when the patient is awake.Such device initialization may also be provided with sensors and/ordetection incorporated into the stimulation device or its peripherals.Also such device initialization may be provided periodically or on anongoing basis during the term of device usage. The device may beprogrammed to adjust stimulation parameters or protocol during thedevice usage term.

Such initialization may also be used to select a type of stimulation orstimulation protocol that is most effective for an individual'sparticular disorder, disease or breathing/disordered breathing. Suchinitialization may also be used to initialize detection

Various detection algorithms may also be incorporated into the device todetect various conditions and/or trigger therapy. The device may beprogrammed to respond with adjustment, switching or turning on or off ofstimulation based on various detections.

According to one aspect of the invention, an increase in FRC or a lungvolume bias may be used for therapeutic purposes prior tomaterialization of an apnea event where breathing instability ispresent, even when no event is present or clearly imminent. According toone aspect, if then a central or obstructive apnea does occur, thedevice may either turn off stimulation, or provide stimulation accordingto a different protocol. Occurrence of an event or pattern of events maytrigger stimulation to prevent future events.

Detection may comprise detecting flow limitations or unstable breathingthat are not at an apnea level and turning on diaphragm stimulation toprovide stability, improving gas exchange or ventilation to reduce flowlimitation or stabilize breathing. For example obstructive apneapatients, unstable breathing or degree of flow limitation may bedetected, or other indicators of a likelihood of obstruction occurring,for example the previous occurrence or pattern of occurrence of events.Stimulation may be accordingly be provided to increase functionalresidual capacity or provide a lung volume bias. If obstructive apneaoccurs, stimulation may be turned off. Turning off stimulation may alsobe used to increase upper airway patency with increased exhalation or toincrease airflow. Where a patient suffers from central apnea or mixedapneas, absent such event stimulation may be provided to increasefunctional residual capacity or provide a lung volume bias to regulateor manipulate gas exchange, improve ventilation and/or stabilizebreathing to reduce conditions that lead to overshooting of respiratorydrive as well as improving upper airway patency. If central apnea isdetected then paced breathing may be provided until normal breathingresumes. After an arousal, a pattern of instability or flow limitations,or apnea event has occurred, stimulation may be turned on to preventsubsequent events. In accordance with this aspect of the invention,detection of apnea events, flow limitations or other respiratorydisorders or instability may trigger turning on or off of therapy.Therapy may then be provided for a period of time or based on a detectedrespiratory state or otherwise controlled in a closed loop system.

According to one aspect of the invention, stimulated lung volume bias isa supplemental increase in lung volume that may be provided withintrinsic, paced or augmented breathing. It may also be provided withother breathing control scenarios.

According to another aspect of the invention, a first type ofstimulation may be provided and subsequently switched to another type ofstimulation. Such switch in stimulation type may be based on, forexample, a determination of effectiveness or lack of effectiveness ofthe first type of stimulation or a change in condition.

According to one aspect of the invention a biased lung volume may beprovided before, during and/or after other diaphragm stimulation amongother things, to help avoid upper airway closure. Such other diaphragmstimulation or stimulation types may include for example, pacedbreathing, augmented breathing, deep inspiration stimulation, breathingcontrol or manipulation of breathing, as well as high frequencycontraction stimulation. According to another aspect of the invention abiased lung volume may be provided before other diaphragm stimulationamong other things, to help avoid upper airway closure. According toanother aspect of the invention a biased lung volume may be providedafter other diaphragm stimulation among other things, to help avoidupper airway closure. According to another aspect of the invention abiased lung volume may be provided throughout other stimulation or aportion of other stimulation.

According to another aspect of the invention stimulation providing abiased lung volume may be turned off to increase upper airway patencywhere the sudden change in pleural pressure or outflow creates anopening of the upper airway prior to the next breath.

These and other aspects of the invention are set forth in thespecification and claims herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1C schematically illustrate lung volume, stimulation of theright hemidiaphragm and stimulation of the left hemidiaphragmrespectively with a ramped up stimulation for creating lung volume biasand a ramped down stimulation.

FIGS. 2A to 2C schematically illustrate lung volume, a first stimulationsignal at a first electrode and a second stimulation signal at a secondelectrode illustrating gradual ramping of stimulation and alternatingstimulation at different locations.

FIGS. 3A to 3C schematically illustrate lung volume, a first stimulationsignal at a first electrode and a second stimulation signal at a secondelectrode illustrating gradual ramping of stimulation and alternatingstimulation at different locations.

FIG. 4 is a flow diagram illustrating device initialization to achievedesired increase in FRC and/or sustained lung volume bias.

FIGS. 5A to 5C are flow diagrams illustrating detection and therapy inaccordance with the invention.

FIGS. 6A to 6C respectively schematically illustrate EMG, EMG envelopeand tidal volume of a subject over varying degrees of airway patency.

FIG. 6D is a power spectral density diagram for three EMG signalscorresponding to varying degrees of airway patency.

FIG. 6E is a schematic diagram of EMG envelope under differentconditions.

FIGS. 7A to 7C schematically illustrate flow, lung volume andstimulation respectively in accordance with one aspect of the invention.

FIGS. 8A to 8C schematically illustrate lung volume under differentconditions and using different levels of bias stimulation.

FIGS. 9A to 9D schematically illustrate flow, EMG envelope, lung volumeand stimulation respectively in accordance with an aspect of theinvention.

FIGS. 10A to 10C schematically illustrate snoring (in decibels) tidalvolume and stimulation respectively in accordance with an aspect of theinvention.

DETAILED DESCRIPTION

In accordance with one aspect of the invention slow gradual ramping upof stimulation is provided over the course of a period of time greaterthan a period of one inspiration cycle, or over the course of timespanning multiple breaths. For example, while not intending to belimited thereto, ramping may be provided over a period of about 5 to 60seconds. The ramping up described may reduce arousals or waking frompatient detection of stimulation. It is believed that among otherthings, ramping may improve patient comfort by producing more gradualdiaphragm contraction and more gradual pressure changes. It is alsobelieved that ramping may reduce the possibility of obstruction that mayoccur with a greater negative thoracic pressure.

Ramping describe herein may be titrated base on patient feedback such assensation, or in a sleep lab.

FIGS. 1A to 1C illustrate a lung volume bias stimulation being ramped upand then down over a period of multiple breaths. The amplitude,frequency, pulse duration, burst duration, and/or burst frequency, maybe modulated or ramped or slowly increased as schematically illustratedin FIGS. 1B and 1C. FIG. 1B illustrates a stimulation signal envelope130 for stimulation of a right hemidiaphragm. The stimulation signalenvelope 130 comprises a ramped portion 135 schematically illustratingthe ramping up of the right hemidiaphragm signal over a plurality ofbreaths 121. FIG. 1B further illustrates a ramped portion 139schematically illustrating ramping down of the right hemidiaphragmsignal over a plurality of breaths 121. FIG. 1C illustrates astimulation signal envelope 150 for stimulation of a left hemidiaphragm.The stimulation signal envelope 150 comprises a ramped portion 155schematically illustrating the ramping up of the left hemidiaphragmsignal over a plurality of breaths 121. FIG. 1C further illustrates aramped portion 159 schematically illustrating ramping down of the lefthemidiaphragm signal over a plurality of breaths 121. Stimulation to theright and left hemidiaphragms are generally synchronized as illustratedin FIGS. 1B and 1C. FIG. 1A illustrates a corresponding lung volume.Breaths 121 as illustrated in FIG. 1A are intrinsic breaths. However,ramping up and down of lung volume bias stimulation as illustrated inFIGS. 1B and 1C may also be used during paced breathing. A baseline lungvolume 120 (initial functional residual capacity) is shown prior tostimulation. During the period of ramping stimulation 122, functionalresidual capacity is gradually increased from the baseline 120. Once thestimulation has been ramped, stimulation is leveled off for period 123.Stimulation is then ramped down for period 124 where functional residualcapacity gradually decreases.

The gradual ramping periods 122 and 124 may be for a period greater thana normal intrinsic inspiration period or over a period spanning aplurality of breaths. While a lung volume bias is illustrated, otherstimulation may be ramped up or down in accordance with an aspect of theinvention.

In accordance with one aspect of the invention, a gradual increase inthe duty cycle of bias situation may also be provided. The duty cyclemay be independent of intrinsic respiration or may be synchronized withbreathing.

In accordance with one aspect of the invention slow gradual ramping upof stimulation is provided with the stimulation offset between twohemidiaphragms or between two or more electrodes or electrode pairs.FIGS. 2A to 2C illustrate a lung volume bias stimulation being ramped upover a period of multiple breaths with ramping offset betweenhemidiaphragms. Stimulation may also be ramped down in an offset manner.The amplitude, frequency, pulse duration, burst duration, and/or burstfrequency, may be modulated or ramped or slowly increased asschematically illustrated in FIGS. 2B and 2C. FIG. 2B illustrates astimulation signal envelope 230 for stimulation of a righthemidiaphragm. The stimulation signal envelope 230 comprises a rampedportion 235 schematically illustrating the ramping up of the righthemidiaphragm signal for a period 222 over a plurality of breaths 221.FIG. 2C illustrates a stimulation signal envelope 250 for stimulation ofa left hemidiaphragm. The stimulation signal envelope 250 comprises aramped portion 255 schematically illustrating the ramping up of the lefthemidiaphragm signal for a period 223 over a plurality of breaths 221.Stimulation to the right and left hemidiaphragms are offset asillustrated in FIGS. 2B and 2C. The periods 222 and 223 are offset fromeach other but overlap in time. Alternatively, the periods 222, 223 maybe sequential. FIG. 2A illustrates a corresponding lung volume. Breaths221 as illustrated in FIG. 2A are intrinsic breaths. However, ramping upand down of lung volume bias stimulation as illustrated in FIGS. 2B and2C may also be used during paced breathing. A baseline lung volume 220(initial functional residual capacity) is shown prior to stimulation.During the periods of ramping stimulation 222, 223 functional residualcapacity is gradually increased from the baseline 220. Once thestimulation has been ramped, stimulation is leveled off at bothhemi-diaphragms for a period of time. The gradual ramping periods 222and 223 may individually or in the aggregate be for a period greaterthan a normal intrinsic inspiration period or over a period during aplurality of breaths. While offset ramping is shown with respect toelectrodes at two different hemidiaphragms, such offset ramping may beprovided with any two or more electrodes or electrode pairs, whetherpositioned on the same hemidiaphragm or not. Offset ramping may beprovided with more than two electrodes or electrode pairs where rampingoccurs in the aggregate for a period greater than that of a normalintrinsic inspiration or for a period spanning multiple breaths.

The gradual ramping periods 222 and 223 may be for a period greater thana normal intrinsic inspiration period or over a period spanning aplurality of breaths. While a lung volume bias is illustrated, otherstimulation may be ramped up or down in accordance with an aspect of theinvention. Offset stimulation may also be used to prevent fatigue byresting stimulated portions of the diaphragm or phrenic nerve whilemaintaining stimulation on.

In accordance with one aspect of the invention switching of stimulationfrom one hemidiaphragm, electrode or electrode pair to another isprovided. According to one aspect, stimulation is provided in a mannerthat maintains a therapeutic diaphragm contraction. FIGS. 3A to 3Cillustrate a lung volume bias stimulation over a period of multiplebreaths with ramping up of one hemidiaphragm and ramping down of theother hemidiaphragm. The amplitude, frequency, pulse duration, burstduration, and/or burst frequency, may be modulated or ramped or slowlyincreased as schematically illustrated in FIGS. 3B and 3C. FIG. 3Billustrates a stimulation signal envelope 330 for stimulation of a righthemidiaphragm. The stimulation signal envelope 330 comprises a rampedportion 335 schematically illustrating the ramping down of the righthemidiaphragm signal for a period 322 over a plurality of breaths 321.FIG. 3C illustrates a stimulation signal envelope 350 for stimulation ofa left hemidiaphragm. The stimulation signal envelope 350 comprises aramped portion 355 schematically illustrating the ramping up of the lefthemidiaphragm signal for a period 323 over a plurality of breaths 321.The periods 322 and 323 overlap in time. FIG. 3A illustrates acorresponding lung volume. Breaths 321 as illustrated in FIG. 3A areintrinsic breaths. However, ramping up and down of lung volume biasstimulation as illustrated in FIGS. 3B and 3C may also be used duringpaced breathing. A baseline lung volume 320 (initial functional residualcapacity) is shown prior to stimulation. During the periods of rampingrespectively down and up of stimulation 322, 323, functional residualcapacity is generally maintained above the baseline 320. The gradualramping periods 222 and 223 may individually or in the aggregate be fora period greater than a normal intrinsic inspiration period or over aperiod during a plurality of breaths. While switched ramping is shownwith respect to electrodes at two different hemidiaphragms, suchswitched ramping may be provided with any two or more electrodes orelectrode pairs, whether positioned on the same hemidiaphragm or not.Switched ramping may be provided with more than two electrodes orelectrode pairs providing overlapping stimulation with differentelectrodes or electrode pairs to permit rest of the diaphragm or nerveassociated with an electrode or electrode pair.

The gradual ramping periods 322 and 323 may be for a period greater thana normal intrinsic inspiration period or over a period spanning aplurality of breaths. While a lung volume bias is illustrated, otherstimulation may be ramped up or down in accordance with an aspect of theinvention. This stimulation may be used to prevent fatigue by restingstimulated portions of the diaphragm or phrenic nerve while maintainingstimulation on.

In accordance with one aspect of the invention, stimulation is providedby varying one or more stimulation parameters, e.g., amplitudes,frequencies, pulse widths and/or burst durations or burst frequencies,stimulation on/off periods, to avoid fatigue or adaptation. Suchstimulation parameters may be within a desired range or may be alteredto provide an optimization of diaphragm rest and diaphragm activation.Such stimulation protocol may be generally open loop where apredetermined program or sequence is used for preset time periods tostimulate and also provide rest. Stimulation may be cycled throughdifferent amplitudes and/or frequencies. Such stimulation protocol mayalso be generally closed loop where stimulation parameters are adjustedbased on feedback indicating rest is needed or that adaptation isoccurring. Stimulation may also be adjusted or cycled on or offdepending upon a patient status, such as, for example, sleep statestatus, or other condition or status. Such protocol may be a combinationof open loop and closed loop wherein stimulation is provided for aperiod of time according to a protocol and then sensing is used toperiodically determine stimulation and response status. For example,after a period of stimulation, detection or sensing may be used todetermine if breathing is continuing to be stabilized after stimulation.Stabilized ventilation may be detected using methods and devices thatdetermine variations in lung volume, tidal volume, functional residualcapacity, flow, or other respiration parameter. Examples of detectionare described in further detail herein or in related applications as setforth herein. Upon detection of stabilized ventilation, stimulation maybe cycled off. Stimulation may be provided again when breathingstabilization has fallen off.

In accordance with one aspect of the invention, stimulation may beindividualized on a patient by patient basis by determining individualpatient response to stimulation, that will achieve a desired result. Forexample, polysomnography may be used to provide therapeutic and/ordiagnostic data on individual patients by observing a patient's sleepdata and by observing a patient's response to therapy. Specific types oftherapy, combinations of therapy and/or therapy parameters may betitrated during polysomnography studies or during an initialization orreprogramming period after implant. Specific types of stimulation and/orcombinations have been set forth herein and in related applications asset forth herein. A number of polysomnography markers may be used todetermine effectiveness of stimulation or combinations of stimulationsuch as: volume changes, stability of flow, removal of flow limitation,FRC, volume, arousals, arousals in response to or due to stimulation,AHI, SaO2 levels. Polysomnography may be used for decisions orinitialization for bias therapy, therapy where FRC is increased, or forusing other therapies such as paced breathing, breathing control,augmented breathing, deep inspiration, duty cycle manipulation or othersfor exampled as described in co-pending applications set for the herein.

In accordance with an aspect of the invention, initialization, forexample, may provide a determination of a desired therapeutic functionalresidual capacity or change in functional residual capacity to beachieved from stimulation. According to an aspect normal lung volumelevels may be determined such as a normal or non-pathological tidalvolume and functional residual capacities may be determined. Lungvolumes may then be observed prior to respiratory disordered events forexample prior to flow limitations, arousals or apneas occurring.Therapeutic stimulation may be provided to raise lung volume to anon-pathological or normal level. Based on initialization data, lungvolume bias therapy or other therapy such as breathing augmentation orother therapy to maintain minute ventilation above the critical levelmay be provided when the critical threshold has been reached. Minuteventilation may be calculated on a breath by breath basis, as a runningaverage or over a predetermined period of time. Thus drops in tidalvolume, FRC or minute ventilation may trigger therapy where no apnea ispresent.

In accordance with another aspect of the invention, ranges of normaland/or out of range parameters may be set based on initialized dataacquisition and analysis.

In accordance with one aspect of the invention, the change in lungvolume from awake to sleep may be observed and set as a therapeutic lungvolume.

According to one aspect, using polysomnography data, a calculation maybe made as to when or at what minute ventilation the patient's SaO2levels drop below a critical level. Such critical level may be definedas a level sufficiently before apnea occurs (Alternatively it may bedefined as a level approximately when apneas occur).

Also, a maximum lung volume or minute ventilation may be set forexample, where therapy may be turned off. Such maximum level may be set,for example as a normal lung volume level plus a percentage of normallung volume (e.g., tidal volume or FRC). Alternatively a maximum minuteventilation may be determined and set as a normal level plus apercentage of such level. Minimum and maximum SaO₂ levels may also beset. SaO₂ may be observed in sleep studies and corresponding to otherparameters such as minute ventilation, lung volume and/or FRC. Or duringtreatment, such levels may be detected. Thus if with stimulation tidalvolume, minute ventilation, SaO₂ or other physiological parameterexceeds a desired or safe level, stimulation may be turned off oradjusted. Also if a normal level of breathing resumes on top ofstimulation, such lung volume or minute ventilation levels may exceed adesired level and stimulation may be turned off or the patient weanedoff of stimulation. In accordance with one aspect of the invention aclinical protocol may be defined where different FRC increases aretested until a satisfactory improvement in disease state is obtained.Such as reduced respiratory disturbances or events, improved SaO₂levels, improved breathing or improved cardiovascular function.

According to another aspect an external programming device may beprovided with software that calculates a recommended therapeutic volumeincrease based on patient's weight, sex abdominal and neck diameter andAHI. This may be used as an initial value which may then be furthertitrated.

Detection as well as therapy parameters may be individualized on apatient by patient basis where patient stability markers are determinede.g. using polysomnography data (for device initialization and/or deviceprogramming updating). Stability markers may include parameters orcombination of parameters that are used to create detection criteria forunstable breathing. For example, polysomnography data may be recordedfor a period of time where normal breathing is occurring. Ranges ofnormal variations in respiratory parameters may be defined. Astatistical analysis may be used to determine or define a range ofnormal parameters or combinations of parameters. Also, the changes thatoccur with the onset of disordered breathing can be quantified and usedto initialize detection criteria, thresholds or ranges.

Referring to FIG. 4, a flow diagram illustrates an example ofindividualizing stimulation to provide a desired functional residualcapacity or biased lung volume. An initial estimate of an optimum FRCincrease is determined based on patient characteristics 410. Suchcharacteristics for example, may be height, sex, BMI, breathing pattern(such as a breathing pattern prior to or leading to an obstruction orother disordered event) or AHI as determined from sleep study. Anothercharacteristic or pattern that might be observed is a percent ofhypopnea events versus apnea. This information may be used to tailortreatment, for example by setting FRC target higher where there aregreater numbers of apneas and lower where there are fewer. Stimulationis then provided to the diaphragm or phrenic nerve 420 using thetherapeutic device. Lung volume change is then sensed, observed ordetermined including change in functional residual capacity 430 eitherin synchrony with stimulation or lasting for a period after stimulation.For example, the change in FRC produced by stimulus may be observedusing a belt with sensors that measure the displacement of the chest andabdomen. A magnetometer may be used to measure chest wall displacement,which is correlated with lung volume, or a measurement of esophagealpressure may be used in order to determine a change in intrapleuralpressure indicative of a lung volume change. Then it is determinedwhether the lung volume change is at a desired level or not 440. If itis not, then the stimulation is adjusted or titrated 450. This titration(or stimulation with the device) may also be done for the left and righthemidiaphragms individually or together in order to achieve the desiredvolume change. In addition, stimulation during initialization or deviceuse that is provided may be unilateral using either right or leftdiaphragm alone. If the desired FRC is achieved, then the patient isobserved in sleep in a clinic at home collecting sensed data includingthat typically observed during polysomnography studies 460 using thetitrated parameters. Information may be telecommunicated as well. Thenit is determined whether the therapy achieved a desired clinical resultwith the initialized stimulation parameters using the polysomnographydata or sensed data 470. Typically such observations may be air flow,EEG, abdominal and rib movement, snore sensor, and SaO2 that determinethe occurrence of apnea or hypopnea events (e.g. apnea/hypopnea index(AHI)), breathing stability, arousals, oxygen saturation, presence ofsnoring or any other data that indicates effectiveness of therapy. Apolysomnography study may show criteria such as improvement in AHI,arousal index and SaO2 saturation levels. Additionally or alternatively,a sleep study without applied therapy may be used as a control todetermine if the stimulation using particular parameters or protocolsresulted in an improvement in any of the clinical parameters observed onthe polysomnograph. If the therapy did not achieve the clinical result,the stimulus is titrated. The titration may be done incrementally duringone or more studies, or it may be adjusted based on informationaccumulated from the previous titration. For example, earlier titrationsmay provide information concerning the dose response, or stimulationparameters associated with corresponding volume change. If the therapydid achieve the desired clinical result, then the stimulation parametersare set or programmed into the therapeutic device 480 until the deviceis reprogrammed. In accordance with one aspect of this example, minuteventilation or other respiratory parameters may be observed and used inaddition or as an alternative to using lung volume, for example in step430.

During a sleep study prior to device implant, data may be collected thatincludes a diaphragm EMG signal. The signal may be recorded and analyzedduring different respiratory states such as flow limitation,obstruction, reduced central drive, and central apnea. This analysis maybe used to set EMG based thresholds for detection of these conditions orevents. For example, the EMG envelope may be calculated, and the widthof the envelope may be determined for each of these conditions. Usingstatistical methods, thresholds may be determined based on EMG envelopewidth that differentiate, for example, flow limitation from obstruction,or normal breathing from reduced central drive. A diaphragm EMG may beused to correlate changes in EMG to a specific respiratory disorder,disturbance or disease on the EMG.

To reduce arousals due to stimulation, stimulation parameters may bemodified such as stimulation frequency, stimulation amplitude orstimulation ramping. This may be implemented, for example at or prior todevice implant. Also stimulation to one or other hemidiaphragm may beadjusted.

Other information may be used to determine adaptation to stimulationwhere the stimulation may be more effective or less effective, orfatigue where the stimulation is less effective. Modification ofstimulation parameters may provided in response to such fatigue oradaptation. Such adjustment of parameters may be provided by monitoringpatient response over time or in a device with continuous or periodicfeedback and adjustment of parameters based on response to stimulation.

Device initialization may be provided with input from external ortemporary sensors, for example in a polysomnography study, or whereappropriate when the patient is awake. Such device initialization mayalso be provided with sensors and/or detection incorporated into thestimulation device or its peripherals. Also such device initializationmay be provided periodically or on an ongoing basis during the term ofdevice usage. The device may be programmed to adjust stimulationparameters or protocol during the device usage term.

In addition to sensing EMG, for initialization or detection, ECG may besensed, e.g., from the implanted device, and the data used to initializethe device or provide feedback during device use. Heart ratevariability, Heart rate RR intervals, may be sensed with sleep datagathered for a night and analyzed for device initialization orprogramming or reprogramming.

An implantable device may match its sleep disordered breathing detectionwith an automated sleep scoring system (for example Morpheus of SleepMedinc. has such an automated scoring system) may be used to calibrateimplant as well.

Various detection algorithms may also be incorporated into the device.The device may be programmed to respond with adjustment of parameters orturning on or off of stimulation based on various detections. Detectionand detection thresholds may be based on data polysomnography or datagathered in a real time therapy device

According to one aspect of the invention, an increase in FRC or a lungvolume bias may be used for therapeutic purposes prior tomaterialization of an apnea event where breathing instability ispresent. Accordingly detection may comprises detecting flow limitationsor unstable breathing that are not at an apnea level and providingstability, improving gas exchange or ventilation to avoid apnea. Thedevice may also detect an imminent apnea event or onset of an apneaevent. If a central or obstructive apnea does occur, the device mayeither turn off stimulation, or provide stimulation according to adifferent protocol. The device may also detect an apnea event or eventsthat may indicate possibility of subsequent events occurring and mayturn on stimulation after an apnea event has resolved.

Table I is a chart illustrating examples of conditions that may bedetected to trigger a therapy. Detection of one or more conditions mayindicate a respiratory disturbance and/or an imminent disordered eventoccurring. It is believed in accordance with the invention that avariety of diseases, disorder or conditions can be treated or preventedusing one or more stimulation therapies including those described hereinand in related applications as set forth herein. It is also believedthat therapies that stabilize breathing, assist in maintainingrespiratory drive at a desired level and/or reducing flow limitationshelps reduce arousals prevent onset of respiratory events such as CheyneStokes Respiration or one or more types of apnea.

According to one aspect, one or more respiratory disturbances orindicators is detected and a first treatment is provided in response.Onset of a disordered breathing event such as an apnea may be detected,then a second treatment protocol may be implemented or the firsttreatment may be modified. Alternatively, occurrence of a disorderedbreathing event such as an apnea may be detected then a second treatmentprotocol may be implemented or the first treatment may be modified.

While not intending to be limiting, Table I provides an examples ofindicators that may be detected. These indicators may be detected, forexample, by sensing one or more respiration parameters as describedherein or in one or more related patent applications as set forthherein.

Conditions to Detect Conditions that Indicate Respiratory DisturbancePossible Indicators of Condition Instability of Breathing Greater thannormal variation of breathing rate, TV, or FRC Reduction in CentralReduced diaphragm EMG (i.e. area under Drive the “envelope”) FlowLimitation Increased amplitude, width and frequency content of diaphragmEMG; change, e.g., flattening of morphology Previous Central or Recentevents: EMG below threshold for Obstructive Apnea breath detection,amplitude, width and Events frequency content of diaphragm EMG overthreshold for obstructive apnea Imminent Disordered Event Sleep data toidentify indicators of imminent disordered event including respiratoryparameters, blood gas levels or other physiological parametersidentified from sleep data observation Airway obstruction (or Furtherincrease amplitude, width and Disordered Event Onset) frequency contentof diaphragm EMG, over that of flow limitation Central apnea(or EMGamplitude that is below threshold for Disordered Event Onset) breathdetection.

Detecting unstable breathing and providing stimulation such as, forexample, bias, augmentation, paced breathing or breathing control maytreat one or more diseases, disorders of conditions associated withunstable breathing and may prevent disordered breathing events. Unstablebreathing may be detected by sensing a greater than normal variation inone or more respiratory parameters. It also may be detected for exampleby sensing snoring, for example as described in more detail herein.Patterns of breathing instability may be observed. For example ifbreathing instability occurs through out the night or increases, thenstimulation may be provided or tailored to that pattern to reduce theoccurrence of unstable breathing or related events.

Detecting a reduction in central drive and providing stimulation such asbias may prevent an obstructive event that can occur during or followinga reduction in central drive. Also augmenting breathing or pacingbreathing may be used to treat a reduction in central drive. Reductionin central drive may be detected by observing drops in tidal volume orslope of tidal volume waveform or one or more parameters of the EMGcomplex. In accordance with one aspect an average tidal volume over aperiod of time may be calculated. A threshold may be determined based onthat average below which a drop in tidal volume or a drop in flow isdetected. The tidal volume or current flow will be compared to thatthreshold. If it is less than the threshold, then a reduction in centraldrive is detected. Detection occurs when a drop in tidal volume or flowoccurs. This allows the start of stimulation before onset of anobstructive episode or central episode.

Detecting a flow limitation and providing stimulation such as describedherein may be used to reduce flow limitations and possible sleepdisordered events. A flow or EMG template may be recorded during flowlimitation at initialization. Then during device operation the currentflow or one or more parameters of an EMG waveform may be compared to thetemplate. If there is a close enough match to the template then a flowlimitation is detected. Additionally, flow limitation may worsen overtime. A threshold may be set based on the degree of limitation andnumber of flow limitation episodes that are observed.

Detection of the occurrence of a previous disordered events may be usedto trigger therapy or to prevent subsequent events. For example after anevent or pattern of events have occurred, stimulation may be turned onto increase functional residual capacity to reduce the likelihood offurther events occurring. Other stimulation may also be triggered aswell, by detecting events that have occurred. There may be a thresholdset such that a certain number of events must occur before therapy isdelivered.

Detecting the imminent onset of a disordered event may trigger therapysuch as bias therapy to prevent the event from occurring. Bias therapymay reduce instability, improve gas exchange while permitting intrinsicbreathing to continue. Sleep data to identify indicators of imminentdisordered event may include changes in respiratory parameters such asin flow, tidal volume, FRC, blood gas levels, certain slope of drop intidal volume, or other physiological parameter changes that occurimmediately prior to an obstructive event. Patterns of change or valuesof such parameters, identified from sleep data observation may be storedas data. Then parameters from one or more breaths may be observed andanalyzed, searching for a repetition of the pattern.

A further increase in amplitude, width and/or frequency content ofdiaphragm EMG, over that of flow limitation may be used to detect anobstructive event. Recordings of a known EMG during obstruction may alsobe used as a template for comparison to a current template to detect andobstructive event. For example, if more than a certain number ofparameters of the template similar within a given percent margin, thenOSA will be detected.

If an EMG amplitude is below a threshold for breath detection, a centralevent may be detected. Stimulation may be turned off to preventobstructions, or paced breathing may be provided.

FIG. 5A is a flow chart illustrating detection and treatment using adevice or method in accordance with one aspect of the invention. One ormore respiration parameters are monitored 510. One or more conditionsare detected indicating a respiratory disturbance 515. Therapy is turnedon to increase FRC or to create a lung volume bias 520. One or morerespiration parameters are then monitored 525 to determine ifrespiration is stable 530. If respiration is not stable, the lung volumebias or therapy to increase FRC is adjusted according to a protocol 535.If respiration is stable then after respiration has been stable for apredetermined period of time 540, therapy is turned off of the patientis weaned off of therapy 545. If respiration is not stable for thepredetermined period of time 540 then the respiration parameter ismonitored again to detect stable respiration 525 and 530.

In accordance with another aspect of the invention as illustrated inFIG. 5B, a second detection may be added to the detection and treatmentof FIG. 5A. If the second detection is added, then at step 535 ifrespiration is not stable and if a second condition is detectedindicating an onset or an imminent or present respiratory disorderedevent or if a determination is made that previous therapy is not leadingto respiratory stability 546, then therapy is adjusted or a secondtherapy is provided 550. One example of such adjustment may be, forexample, if flow limitation still is detected after bias stimulation,stimulation may be switched to a stimulation protocol to increaseinspiration duration.

One or more respiratory parameters are monitored 555. If respiration hasnot stabilized 560 then therapy is adjusted according to a protocol 565and respiration is monitored again at step 555. If respiration is stablethen if respiration has been stable for a preset period of time 570therapy is turned off of the patient is weaned from the therapy 575respiration is then monitored again at step 510 (FIG. 5A). Ifrespiration has not been stable for a preset period of time 570 thentherapy is returned to step 555. An example of a second therapy may bepaced breathing if a central apnea is detected or a turn off of therapyif an obstruction is detected. The step of detecting if a secondcondition is present may also determine such second condition from oneor more types of conditions. For example detecting the second conditionmay detect obstructive apnea or central apnea and determine which typeof apnea is occurring or has occurred. If at step 546 a second conditionis not detected indicating an onset or an imminent or presentrespiratory disordered event and if a determination is not made thatprevious therapy is not leading to respiratory stability, then return tostep 525

FIG. 5C is a flow chart illustrating detection and treatment for upperairway flow limitation or obstruction. Detection parameters areinitialized 580, e.g., in a manner as set forth herein. The EMG complexis processed and monitored 581 to determine if a flow limitationthreshold has been crossed 582, for example, as described in more detailwith respect to FIGS. 6A-6E herein. If the threshold for flow limitationhas not been crossed then monitoring continues at step 581. If thethreshold for flow limitation has been crossed 582, then it isdetermined whether the flow limitation has also crossed the thresholdfor airway obstruction 583. If there is an airway obstruction, then thetherapy is turned on, turned off or adjusted according to a protocolwhere appropriate 584 until the end of the obstruction 585 after whichmonitoring resumes at step 581. If at step 583, a threshold has not beencrossed for airway obstruction then the appropriate therapy is turned onand a timer is set 586. The EMG complex is then monitored and processed587. It is then determined if the response to the therapy is acceptable588. If it is not, then therapy is adjusted 589 and monitoring continuesat step 587. If the response to the therapy is acceptable at step 588,then if a timeout (preset time period) has not been reached 590monitoring continues at step 587. If the response to the therapy isacceptable at step 588 and a timeout has been reached at step 590, thenthe patient is weaned off of the therapy 591 and monitoring begins againat step 581.

In addition to using detection of respiratory instability, respiratorydisorders or imminent onset of a respiratory disorder to triggertherapy, therapy may be triggered after an event (or a number of events)has occurred such as an obstructive or central event. According to anembodiment, detection of an arousal may trigger delayed turning on ofbias stimulation. Bias stimulation may then be turned on for a period oftime. An occurrence of an event or events may indicate that a patient ismore susceptible to additional events occurring and a therapy such as abias therapy may be turned on for a predetermined period of time. Anumber of physiological conditions may increase likelihood of eventssuch as onset of sleep or a particular sleep state. Detection of suchevents may also be used to trigger therapy where the events are known toincrease a patient's susceptibility to apneas or other respiratorydisorders.

A patient's episode patterns may be observed and therapy type orcombinations of therapies may be selected. During polysomnography studyfor device initialization, a number of different therapies orcombination may be evaluated or titrated based on observed patternsbefore or resulting from tested or trial therapy. If, for example, thereis a tendency for central or mixed apneas, detection or therapy may bekeyed to specific patient pattern. A type of therapy for a particularpattern may be selected, for example if the event is primarily central,a particular therapy may be selected; if the event starts as anobstructive event and then continues as a central event another therapymay be selected. For example, if a patient has a tendency to have eventsthat are obstructive or flow limited followed by mixed events, biastherapy may be turned on at an early indication of breathinginstability, to stabilize breathing by improving stability of the upperairway or of flow. In a patient with disordered breathing that tends tobe initially centrally mediated, bias may be turned on prior to anevent, followed by stimulation during breathing to augment breathing orpaced breathing to treat the centrally mediated disorder.

In a closed loop system, it may be desirable to avoid turning on duringperiods of severe flow limitation as stimulation during such periods maynot be as efficient particularly where severe airway resistance reducesthe ability of stimulation to increase functional residual capacity.Timing of bias may be synchronized with respiration so that it providesa more efficient increase in functional residual capacity (as the airwayis already opening and breathing is occurring).

In addition to detection set forth above, as a safety mechanism, thedevice may be provided with sensors that confirm that breathing isoccurring on top of bias stimulation

In accordance with another aspect of the invention, sensing may beprovided of external or environmental conditions for example atmosphericpressure changes due to change in altitude. Stimulation or detection maybe adjusted base on such external or environmental characteristics.

In accordance with one aspect of the invention, a plurality ofthresholds are used to determine a plurality of levels of airwayobstruction or flow limitation.

Detection of thresholds for flow limitation and complete obstruction inaccordance with the invention may be determined related to the effort ormagnitude of effort. As effort increases, a number of features in theEMG complex change. EMG envelope has been used to determine effort. TheEMG envelop is obtained using an averaging process. However the EMGenvelope determination process does not take into account all of thedifferent magnitude changes that occur in an EMG complex with anincrease in effort. Such factors include the frequency content changes,the width of the complex increase, increase in rising slope of EMGenvelope and the increase in amplitudes and density of the individualspikes. In accordance with one aspect of the invention, an improveddetection of effort is provided which takes into account one or more ofthe factors of the EMG complex. In accordance with another aspect of theinvention in order to obtain a more accurate determination of effort, aplurality of factors of the EMG complex are used to determine degree ofobstruction or flow limitation. For example, a power spectral densityplot of EMG may be used to determine effort. Also frequency content ofan EMG may be used to determine effort. Because frequency contentincreases with increased effort, the area under the Power SpectralDensity Plot, e.g., between 100 and 500 Hz increases for flow limitedactivation (breath) versus non flow limited activation. A threshold maybe set corresponding to an area under the PSD for detecting flowlimitation or obstruction.

Referring to FIGS. 6A, 6B and 6C, EMG, EMG envelope and tidal volume areillustrated under different levels of flow limitation. The diaphragm EMGas well as upper airway (genioglossal EMG and intercostals show anincreased activity with increased breathing effort. The increasedactivity can be measured through processing of the diaphragm EMG or EMGfrom other respiratory muscles to obtain an EMG envelope for each phasicactivity. The envelope can be created by rectifying the signal,performing a window average over about 100 ms performing peak detectionto obtain an envelope amplitude, and an integration of the area underthe averaged signal to produce an envelope area. This processing toobtain an EMG envelope is generally known in the art. In accordance withone aspect, the phase of the diaphragm EMG with respect to otherrespiratory muscles may indicate obstruction or flow limitation. Inaccordance with one aspect of the invention, the EMG envelop may be usedto differentiate between flow limitation and a greater level ofobstruction. Where there is a flow limitation or flow obstruction,effort increases as does the EMG envelope amplitude. In addition aseffort increases, e.g. due to greater limited flow or increased flowresistance, a number of features in the EMG complex change. Thefrequency content increases, the amplitude of the EMG spikes increases,the rising slope of the EMG complex increases and the width of thecomplex increases and the area under the envelope increases. One or moreof the parameters may be used to identify when there is a flowlimitation or when there is a flow obstruction. One or more thresholdsmay be set to determine one or more of these conditions.

Breaths 601, 602, 603, 604 show a normal EMG with a normal EMG envelopeand a normal tidal volume. Breath 605 shows an increased EMG envelope(FIG. 6B), a reduced tidal volume and an EMG complex (FIG. 6A) withhigher amplitude and components of increased frequency, indicating aflow limitation. Breaths 606, 607, 608 and 609 show a further increasedEMG envelope (FIG. 6B), a further reduced tidal volume and a EMG complex(FIG. 6A) with even higher amplitude and components of increasedfrequency, indicating a flow obstruction. As shown in FIG. 6E the EMGenvelope for a flow limited breath is greater in amplitude and durationfor a flow limited breath 650 as compared to those of a normal breath640. The EMG envelope for a flow obstructed breath 660 is greater inamplitude and duration than the EMG for a lower level flow limitedbreath 650. Thus using an EMG envelope, the increase in the envelope canbe sensed or determined and used to determine when a flow limitation isoccurring at a first threshold, and where an obstruction is occurring ata second threshold. The thresholds may be determined on a patient bypatient basis. The thresholds may also distinguish degrees of flowlimitation as well as flow limitation being distinguished from anobstruction, or either being distinguished form a normal breath.

As shown in FIG. 6D a Power Spectral Density (PSD) plot is illustratedof an EMG complex of a normal breath 610, of an EMG complex of a flowlimited breath 620 and an EMG complex of an obstructed breath 630. Ascan be seen, there is an increase power density of higher frequencycomponents of the EMG as obstruction occurs to a greater degree. Thearea under the PSD curve within a particular frequency range may be usedto determine normal breathing versus flow limited breathing versus upperairway obstruction. Because the frequency content increases withincreased effort, the area under the Power Spectral Density Plot between100 Hz and 500 Hz (or the PSD in that bandwidth) increases as flowlimitation increases. Thus using an EMG signal, the increase infrequency content of the complexes can be sensed or determined and usedto determine when a flow limitation is occurring at a first threshold,and where an obstruction is occurring at a second threshold. Thethresholds may be determined on a patient by patient basis. Thethresholds may also distinguish degrees of flow limitation as well asflow limitation being distinguished from an obstruction or either beingdistinguished form a normal breath.

FIGS. 7A-7C illustrate use of a device and method whereby a biasstimulation is provided for a period over more than one breath andpreferably several breaths.

According to another aspect of the invention, the stimulation is cycledoff (or on) at a preselected portion of a respiration cycle. FIGS. 7A-7Cfurther illustrate use of a device and method whereby a bias stimulationis provided and then is turned off to create a therapeutic benefit. Biasstimulation 750 (FIG. 7C) is provided to thereby increase functionalresidual capacity from a baseline 720 to an increased biased level 730(FIG. 7B). Stimulation is turned off at the end of inspiration or thebeginning of exhalation which provides an increased negative flow 710(FIG. 7A), and increased positive pressure in the upper airway duringexhalation. In accordance with one aspect of the invention, bias iscycled off to provide an increase in upper airway patency.

FIGS. 8A-8C illustrate different levels of increased FRC (e.g. from areference point) achieved by different levels of low level biasstimulation. As can be seen low level bias stimulation can increase FRCin different amounts to achieve a desired therapeutic effect. In FIG. 8Aa baseline FRC 810 is at about 3 Liters of volume above a residual lungvolume 805. Stimulation is turned on at point 815. Stimulation isprovided where functional residual capacity 820 is increased to about3.5 liters, e.g., the FRC change is below the tidal volume 822 of anormal intrinsic breath 821. The FRC is increased by about 0.5 liter or½ of a tidal volume of about 1 liter. In FIG. 8B a baseline FRC 830 isat about 3 Liters of volume above a residual lung volume 825.Stimulation is turned on at point 835. Stimulation is provided wherefunctional residual capacity 840 is increased to about 4 liters, e.g.,approximately at the tidal volume 842 of a normal intrinsic breath 841.The FRC is increased by about 1 liter or about the same as tidal volumeof about 1 liter. In FIG. 8C a baseline FRC 850 is at about 3 Liters ofvolume above a residual lung volume 845. Stimulation is turned on atpoint 855. Stimulation is provided where functional residual capacity860 is increased to about 4.5 liters, e.g., the FRC increase is abovethe tidal volume 862 of a normal intrinsic breath 861. The FRC isincreased by about 1.5 liter or 1½ times a tidal volume of about 1liter.

FIG. 9A illustrates a normal flow (FIG. 9A), a normal EMG envelope (FIG.9B) and normal lung volume (FIG. 9C) at breaths 901, 902 where there isno stimulation (FIG. 9D). Flow is decreasing (FIG. 9A) along with EMGenvelope (FIG. 9B) and tidal volume (FIG. 9C) at breaths 903, 904, 905.Reduced flow, EMG and/or lung volume may be detected and may trigger afirst stimulation therapy. A low level or bias stimulation 920 (FIG. 9D)is then provided during breaths 906, 907, 908, 909 which results in anincrease in functional residual capacity 931 from baseline 930. Thisincrease in functional residual capacity may be therapeutic and mayresult in resumption of improved drive or breathing from improved gasexchange and/or increased upper airway stability due to an increasedfunctional residual capacity. After breath 909, a central apnea eventoccurs. While bias stimulation 920 continues, a paced breath isstimulated 921 to elicit breath 910. Providing bias stimulation beforepaced breathing or continued during paced breathing may furtherstabilize the airway during paced breathing. Such paced breathing maycontinue for a period of time.

Bias stimulation provided before during and/or after other diaphragmstimulation such as breathing control stimulation, augmentation, dutycycle control, paced breathing or other stimulation, for example, asdisclosed in co-pending related patent applications set forth herein.Such bias stimulation may reduce a possibility of upper airway closureduring the other stimulation.

Bias stimulation may be used in combination with paced breathing orother diaphragm stimulation of respiration, to stabilize the upperairway, and avoid obstructions or the need for tracheotomies in patientswho have diaphragm stimulators. For example bias may be used in adiaphragm stimulation device with paralysis patients, ALS patients orother patients who would otherwise need chronic ventilator support.

According to another aspect of the invention a motion sensor or positionsensor may be used to determine a patient's position and adjust thestimulation accordingly. For example, therapy may be turned on for apatient with an obstructive disorder where the patient's events areposition sensitive. For example the therapy may be turned on when thepatient is supine, and the therapy may be turned off when a patientrolls on their side. The stimulation intensity or other parameter may beadjusted depending on a patient's position. The change in position maylead to a change in FRC. Stimulation may be adjusted based on a changein position or a change in FRC. There is also typically a fall in FRCwhen the patient's state changes from awake to sleep. If this volumechange is measured for a patient, it may be used to target a therapeuticvolume. For example, the therapeutic volume increase is the same as theFRC fall when the patient goes to sleep.

In accordance with one aspect of the invention, diaphragm stimulationmay be combined with Autonomic Nervous System (ANS) or vagal or otherparasympathetic activation. In accordance with another aspect of theinvention a device for treating apnea having either a component of OSAor CSA by stimulating the diaphragm or phrenic nerve to elicit adiaphragm response, is combined with a vagal stimulation (or otherparasympathetic activation caused by electrical stimulation.) Forexample, diaphragm/phrenic stimulation may cause an increased FRC orbiased lung volume, or may modify or control breathing. Neuralstimulation to the ANS may also be provided to have an excitatory effecton respiratory drive. Such stimulation may be directly to the centralnervous system or to afferents to the central nervous system.Stimulation to one or the other (diaphragm/phrenic or ANS) may be donesimultaneously or in an alternating manner. A fully implantable devicewith multiple leads may be used or external devices may be used or acombination of both. The advantage of combining two types ofstimulation, for example, may be that the phrenic nerve stimulation maytreat the obstruction or flow limitation by eliciting a mechanicalincrease in lung volume while the parasympathetic stimulation may helpreduce or control sympathetic activation or sympathetic bias that occursduring apnea, to reduce or avoid sharp changes in blood pressure and/orovershooting of respiratory drive that can occur following an apnea.

FIGS. 10A to 10C illustrate an example of an unstable breathing detectorand treatment device in accordance with an aspect of the invention. FIG.10A schematically illustrates output of an audio sensor configured tosense noise or sound associated with snoring. Snoring indicates somedegree of airway obstruction and may be correlated to flow limitation.In the example illustrated, as level of snoring increases at breaths1023, 1024, 1025, a decrease in tidal volume is associated with thesnoring (FIG. 10B). Snoring may decrease again (breaths 1026, 1027) andthen increase again (breaths 1028, 1029) illustrating instability inbreathing and fluctuations in flow and tidal volume. A bias stimulation1050 is provided at 1040 which provides a decrease (breaths 1030, 1031)in snoring and a normalization or stabilization of an intrinsic normaltidal volume where snoring falls below a detectable level (breaths 1032,1033, 1034).

FIGS. 10A-10C schematically illustrate an effect of stimulation onunstable breathing. While a sensor such as an audio sensor isillustrated. The treatment may alternatively be provided without sensoryfeedback or with limited sensor feedback for example that indicates anappropriate time for turning on or off therapy for a predeterminedperiod of time or according to a predetermined protocol.

Additionally, while FIGS. 10A-10C illustrate the use of snoring andtreatment of snoring as well as treatment of unstable breathing. Othertypes or forms of unstable breathing or other indications of unstablebreathing may be used to identify the presence of unstable breathing.For example, unstable breathing may include an above normal variabilityin flow, lung volume, tidal volume, breathing rate, minute ventilation,blood gas levels. Such examples may include, those set forth herein andin related applications as set forth herein.

Stimulation in the various embodiments described herein may be patientor clinician activated. For example, a patient may turn a device onbefore going to sleep. The device may turn on therapy a predeterminedtime after the patient has turned the device on. The patient may also beprovided with an actuation device that delays stimulation when desired,for example for a predetermined period of time. A device may alsoinclude sensors or algorithms that turn the device on or off for periodsof time, for example during sleep or a particular sleep stage. Thedevice may then provide stimulation according to a predeterminedprogram, for example, intermittently during sleep. Such device may beopen loop in that it does not necessarily respond to particularrespiratory events. The device may be closed loop in that it sensesrespiration or other physiological parameters after it has been turnedon to respond or adjust based on the parameters. Examples of closed loopdetection may include those set forth herein and in related applicationsas set forth herein.

Stimulation may be triggered on or off by a user or provider, bydetection of a patient sleep state. The device may be turned on or offin a number of manners including, e.g., patient turn on followed bydelay; patient turn on and an immediate start; turn on based on time ofday; turn on or off based on awake/sleep state; or by detection of anevent (either onset or resolution). The device may also be turned offupon detection of patient waking up or patient manual deactivation.

The device may be turned on or off, or therapy triggered upon detectionof sleep or sleep state. Sleep leads to a number of changes in thebody's autonomic function, and physiological parameters. A number ofthese changes can be detected by the implanted device or externalsensors. Activity level can be detected with an implanted or externallyattached accelerometer, where a decreased activity can be indicative ofsleep. Also, a multidimensional accelerometer can be used to detect thatthe patient is in a sleep or resting position and turn on/off therapy,or put the device into a “waiting state” for detection of breathingdisordered events. In addition, changes in respiratory parameters suchas breathing rate, and minute ventilation can be used to detect sleep.For example, baseline respiration rate and minute ventilation can bedetermined when the patient is in known states, i.e. quiet restingversus sleep. This information could be used to help the device todiscriminate between those states. Also the synchrony of respirationwith cardiac rhythm changes when going from the wake to the sleep state.This would require a learning algorithm where the device would learnthrough recording of baseline data the typical synchrony of therespiration versus the heart rate during sleep, and use this informationin a sleep detection algorithm. The cardiac rhythm alone can be used todetect sleep as well. For example, histograms could be created for heartrate and heart rate variability in the sleeping and waking state, andthese histograms could be used to create reasonable thresholds to allowdifferentiation between sleep and wake, based on heart rate or heartrate variability.

In addition to individual parameters, the criteria for sleep detectionmay be a combination of a number of factors, for instance patientindicating that he is laying down and preparing for sleep, time of day,heart and respiratory rate or pattern. When two or more of the criteriaare met the device may determine that the patient was asleep.

In addition to differentiating between in sleep and awake state, thedevice may differentiate between different stages of sleep. The stagesof sleep include Stage 1, a transitional stage, Stage 2, a light sleepstate, Stage 3 and 4, slow wave or deep sleep, and REM, or rapid eyemovement sleep, where dreaming, muscle paralysis, and a lot ofvariability in sympathetic tone occur. Patients vary according to whichsleep stage most of their disordered breathing occurs. But in mostpatients, REM sleep is where a majority of OSA episodes occur due to thereduced functioning of the upper airway muscles, and stage 3 and 4 arerelatively free of breathing disordered events. Therefore it may beadvantageous for the device to turn on or adjust therapy to a higherlevel at the detection of REM sleep, and turn off or reduce therapy atdetection of stage 3 and 4 sleep.

While the invention has been described in detail with reference topreferred embodiments thereof, it will be apparent to one skilled in theart that various changes can be made, and equivalents employed, withoutdeparting from the scope of the invention.

1. A method of treating a subject who has been diagnosed with centralsleep apnea comprising: providing a first electrical stimulation tocause a diaphragm contraction to thereby elicit a lung volume bias; andsubsequently providing a second electrical stimulation to elicit atleast one breath.
 2. The method of claim 1 wherein the first electricalstimulation is provided after detection of a decreased respiratorydrive.
 3. The method of claim 1 wherein the second electricalstimulation is provided after detection of central apnea.
 4. The methodof claim 1 wherein at least a portion of the first stimulation overlapsat least a portion of the second stimulation.
 5. A method for treating asubject having neuromuscular impairment of the diaphragm comprising:providing a first electrical stimulation to elicit a diaphragmcontraction and thereby elicit a lung volume bias immediately prior to:providing a breathing assist stimulation to elicit diaphragm contractionto increase ventilation of a subject.
 6. The method of claim 5 whereinthe subject having a neuromuscular impairment is a subject havingparalysis impairing diaphragm movement.
 7. The method of claim 5 whereinthe subject having a neuromuscular impairment is a subject having ALS.8. The method of claim 5 wherein the step of providing breathing assiststimulation comprises providing stimulation configured to increase tidalvolume of the subject.
 9. The method of claim 8 wherein the step ofproviding stimulation configured to increase tidal volume of the subjectcomprises providing stimulation to augment intrinsic breathing.
 10. Themethod of claim 8 wherein the step of providing stimulation configuredto increase tidal volume comprises providing stimulation to createbreaths.
 11. A method for treating a subject comprising; providing afirst electrical stimulation to elicit a diaphragm contraction andthereby elicit a lung volume bias immediately prior to or after:providing a second therapeutic electrical stimulation to elicit adiaphragm contraction wherein the second therapeutic electricalstimulation is selected from a group comprising: breathing augmentationstimulation, deep inspiration therapy, increasing inspiration duration;and manipulating duty cycle of inspiration with respect to a respirationcycle.
 12. The method of claim 11 further comprising the step ofproviding the first electrical stimulation during the second electricalstimulation.